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北京大学学报（医学版） ›› 2019, Vol. 51 ›› Issue (3): 390-396. doi: 10.19723/j.issn.1671-167X.2019.03.003

• 工作综述 • 上一篇    下一篇

激活毒蕈碱乙酰胆碱受体调控下颌下腺分泌的机制研究

丛馨1,2,闵赛南3,吴立玲1,2,蔡志刚3,俞光岩3△()   

  1. 1. 北京大学口腔医学院·口腔医院,唾液腺疾病研究中心,　国家口腔疾病临床医学研究中心　口腔数字化医疗技术和材料国家工程实验室　口腔数字医学北京市重点实验室,北京　100081
    2. 京大学基础医学院生理学与病理生理学系,北京　100191
    3. 北京大学口腔医学院·口腔医院口腔颌面外科,北京 100081
  • 收稿日期:2019-03-31 出版日期:2019-06-18 发布日期:2019-06-26
  • 作者简介:俞光岩,北京大学口腔医院口腔颌面外科教授、博士生导师,中华口腔医学会会长。主要研究方向为唾液腺疾病、口腔颌面部肿瘤以及唾液腺移植治疗重症干眼症。先后承担国家及省部级科研基金项目40余项,培养研究生及博士后80余名。率先开展腮腺功能性外科,明显减少手术并发症;提出唾液腺肿瘤临床病理新特点,牵头制定《唾液腺肿瘤诊断和治疗指南》;利用多学科交叉优势,创建了下颌下腺移植治疗重症干眼的关键技术体系并推广应用;完成了全世界病例数最多的下颌下腺移植治疗重症干眼的临床和基础研究;提出激活辣椒素受体调控下颌下腺分泌的新机制以及以受体为靶点人工调控移植下颌下腺分泌的新策略,创立了部分下颌下腺移植预防术后泪溢的新术式和诊治慢性阻塞性移植下颌下腺炎的新技术,明显提高了临床疗效;主持制定了《血管化自体下颌下腺移植治疗重症干眼症的指南》;开展下颌下腺功能保存治疗的系列研究,国内率先开展下颌下腺转位预防放射性口干新术式;建立腮腺和下颌下腺CT体积测量新方法,为腮腺和下颌下腺肿大的诊断提供客观标准;揭示IgG4相关唾液腺炎的临床、病理和影像学特点,建立IgG4相关唾液腺炎的诊断和治疗体系。先后发表SCI论文150余篇,以第一完成人获国家科学技术进步奖二等奖1项、省部级科技进步奖一等奖3项,获“全国五一劳动奖章获得者”“全国卫生系统先进工作者”“全国优秀科技工作者”等称号,并被中国香港牙医师学院、英国爱丁堡皇家外科医师学院和英国英格兰皇家外科医师学院先后授予“Honorary Fellowship”。
  • 基金资助:
    国家自然科学基金(81671005、81771093)

Role and mechanism of muscarinic acetylcholine receptor in the regulation of submandibular gland secretion

Xin CONG1,2,Sai-nan MIN3,Li-ling WU1,2,Zhi-gang CAI3,Guang-yan YU3△()   

  1. 1. Center for Salivary Gland Diseases, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China
    2. Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing 100191, China
    3. Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
  • Received:2019-03-31 Online:2019-06-18 Published:2019-06-26
  • Supported by:
    Supported by the National Natural Science Foundation of China(81671005、81771093)

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关键词: 毒蕈碱乙酰胆碱受体, 下颌下腺, 分泌, 水通道蛋白, 紧密连接

Abstract:

SUMMARY Muscarinic acetylcholine receptors (mAChRs), including M1-M5 subtypes, are classic receptors in regulating water, ion, and solute transport in salivary gland. Our work focuses on the studies on the expression pattern and function of mAChR in the submandibular gland (SMG), and the under-lying mechanism involved in the mAChR-regulated secretion, together with the effect of parasympathectomy on the salivary secretion. Microvascular autotransplantation of SMG into the temporal fossa provides a continuous and endogenous source of fluids, and is currently an effective method for treating severe keratoconjunctivitis sicca. By using RT-PCR, Western blotting, and immunofluorescence, our data demonstrated that the expression of M1 and M3 subtypes were decreased in latent period in rabbit SMG autotransplantation model, whereas carbachol stimulation promoted the salivary secretion, as well as M1 and M3 expressions. By contrast, mAChRs were hypersensitive in epiphora SMGs, whereas atropine gel and botulinum toxin A application significantly inhibited the hypersecretion in both animal models and patients. Furthermore, the possible intracellular signal molecules involved in the mAChR-modulated saliva-ry secretion were explored. Activation of mAChR upregulated the expression of aquaporin 5 (AQP5), the main transporter that mediated water secretion through transcellular pathway, and led to AQP5 trafficking from lipid rafts to non-lipid microdomain. Extracellular signal-regulated kinase 1/2 (ERK1/2) was involved in the mAChR-regulated AQP5 content. mAChR activation also modulated the expression, distribution, and function of tight junction proteins, and increased paracellular permeability. ERK1/2/β-arrestin2/clathrin/ubiquitin signaling pathway was responsible for the mAChR-regulated downregulation of tight junction molecule claudin-4. Cytoskeleton filamentous actin (F-actin) was also involved in the distribution and barrier function of epithelial tight junctions. Besides, endothelial tight junctions were opened by mAChR agonist-evoked salivation in the mice. Furthermore, parasympathetic denervation increased resting salivary secretion in the long terminrats and minipigs. Taken together, our work demonstrated that mAChR regulated saliva secretion via transcellular and paracellular pathways in SMG epithe-lium as well as tight junction opening in SMG endothelium. Modulation of mAChR might be a promising strategy to ameliorate SMG dysfunction.

Key words: Muscarinic acetylcholine receptor, Submandibular gland, Secretion, Aquaporin, Tight junction

中图分类号: 

  • R781.7

图1

激活毒蕈碱乙酰胆碱受体对下颌下腺上皮和内皮细胞物质转运的影响"

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